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Alessandra Tuccitto, Xiaoxin Guo, Jeremy M Sivak; MNK1 Inhibition Protects Retinal Ganglion Cells From ERK Mediated Injury. Invest. Ophthalmol. Vis. Sci. 2018;59(9):4501.
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© ARVO (1962-2015); The Authors (2016-present)
Many neurotoxic stresses inducing retinal ganglion cell (RGC) death converge on mitogen activated protein kinase (MAPK) signaling, including activation of ERK and p38. However, mechanisms induced by these signals are not entirely understood. Activated MAPKs directly phosphorylate the downstream kinase MAPK serine/threonine-interacting kinase 1 (MNK1). MNK1 in turn regulates translation through the eukaryotic translation initiation factor 4E (eIF4E), which binds nearly all capped mRNA before they enter the ribosome. Previous studies show that MNK1 activation elicits a context dependent translational response through eIF4E that regulates cell proliferation and development. In the present study we explored the role of MNK1 activation in neurodegeneration, downstream of MAPK signaling, by modulating eIF4E.
HT-22 neuronal cells were pretreated with small molecule inhibitors of MNK1, eIF4E, ERK, p38, or a DMSO vehicle before application of a glutamate injury to induce cell death. The ERK agonist C6 ceramide was used to induce cell death. Cell viability was then assessed using the XTT assay. To assess if MNK1 inhibition is neuroprotective to RGCs in vivo, we used the kainic acid (KA) injury model in C57BL/6 mice. An MNK1 inhibitor or vehicle was administered intravitreally 1 hour before injection of KA or PBS vehicle. 18 hours after injury, retinas were collected, flatmounted, and stained with the RGC marker RBPMS for confocal microscopy. The number of RGCs per field was quantified.
MNK1 inhibition rescued neuronal cell viability from glutamate injury compared to vehicle (1.75±0.09-fold, p<0.01). Similarly, inhibition of eIF4E resulted in rescue against the glutamate injury (3.28±0.97-fold, p<0.001). Interestingly, ERK (5.35±0.26-fold, p<0.001) but not p38 (1.01±0.46-fold, p>0.05) inhibition was protective against glutamate injury. Inhibition of MNK1 (1.74±0.05-fold, p<0.001) and eIF4E (1.96±0.01-fold, p<0.001) blocked cell death induced by ERK activation. Finally, we demonstrated in vivo that increasing concentrations of MNK1 inhibitor protected peripheral RGCs from KA injury compared to vehicle (30uM: 1.51±0.15-fold, p<0.05; 300uM: 1.55±0.10-fold, p<0.01).
This study provides evidence that an ERK-MNK1-eIF4E signaling axis may contribute to RGC degeneration. Further, this pathway may serve as a novel therapeutic target for metabolic injury in retina and related neurodegenerative processes.
This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.
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